title: Pathway analysis of genome-wide data improves warfarin dose prediction.
abstract: BACKGROUND
  Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations.
  
  
  RESULTS
  Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association.
  
  
  CONCLUSIONS
  Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Daneshjou
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tatonetti
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.forename: Hersh
authors.initials: H
authors.lastname: Sagreiya
authors.forename: Stephane
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Drozda
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Matthew
authors.initials: M
authors.lastname: Tector
authors.forename: Nita A
authors.initials: NA
authors.lastname: Limdi
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: Minoli
authors.initials: M
authors.lastname: Perera
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
mesh_terms: D001741:Black or African American / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases